The present invention relates to a composition for preventing or treating angioedema, such as retinal edema, macular degeneration, and varicose veins, containing an extract of peony root or a mixed extract of peony root and licorice as an active ingredient.
Angioedema is referred to as a disease that due to the increased permeability of blood vessels in the deepest recesses of skin or under skin, or beneath mucous membranes fluids flow out from the blood vessels and pool in surrounding tissues (i.e. edema is caused), and occurs well in relatively loose tissues, with being common around eyes or lips, or in hands and also occurring in tongues, mouths, larynges, mucous membranes such as gastrointestinal tract walls, and in particular blood-retinal barriers are damaged due to angioedema to cause macular edema, retinal edema or macular degeneration, or varicose veins.
Macular degeneration (age-related macular degeneration: AMD) is one of irreversible diseases, which is a representative ophthalmologic disease supervened to the elderly and leading to blindness. Due to population aging worldwide, the incidence is particularly increasing in developed countries. In the United States, macular degeneration is the main cause of blindness and also affected by environmental factors and genetic factors, and especially smoking was reported as the most deadly disease factors. Besides, obesity, and excessive intake of antioxidants and dietary fats also cause macular degeneration and influence to further progress. Therefore, healthy diet intake, weight control, moderate exercise, and no smoking reduce the onset of macular degeneration. The prevalence rate of early (dry) macular degeneration in the United States is about 3.9% in the 40-50 age groups, but 22.8% in the over 75 age groups, which showed to have very greater incidence rate (Beaver Dam Eye Study). Furthermore, it showed 5.4% of the incidence rate in the elderly group over 75 years, 7.1% of which were terminal macular degeneration patients. 1.9% of the Caucasian peoples living in Australia were terminal macular degeneration patients, with showing 0% of the incidence rate in the young age groups of 55 years or less but 18.5% in the elderly groups over 85 years for five years. Also, it was similar for Malay people in Asia (Blue Mountain Eye Study) (Progress in retinal and eye research, 1-15, 2014).
In the case of Korea, the Korean Retina Society reported that for the past year wet macular degeneration patients increased 7.4-fold and the incidence rate in 40, 50 middle-aged and senior adults increased 9-fold (2011). But most seriously, there is no macular degeneration therapeutic agent. Lucentis from Novartis, Switzerland, is an antibody therapeutic agent and very expensive, and it is impossible to stop the disease progression to such an extent as to restore sight.
Macular degeneration is classified as dry macular degeneration and wet macular degeneration. Dry macular degeneration is supervened due to the damaged macula by piling up drusen, which is a waste mass, on macula to damage metabolic connection between choroid and the upper part of macula and thus to damage macula. If this progress continues, it is advanced into wet macular degeneration. That is, since blood vessels function poorly by accumulating wastes in the macular region so that necessaries such as nutrients are not supplied, it starts to create new abnormal blood vessels (choroidal neovascularization: CNV). These generated vessels have very weak walls to leach proteins or red blood cells in the vessels into macular regions and retinas, whereby eventually due to vascular hemorrhage, various factors such as killing rod and cone photoreceptors and retinal pigment epithelial cells are developed to eventually lead to blindness (Nutrition Research, 34, 95-105, 2014; Plos one, 8, e71064, 2013).
Retinal pigment epithelial cells (RPEs) play an important role in maintaining healthy eyes by maintaining non-proliferative state and supporting Bruch's membrane (BrM). Cystatin C secreted from retinal pigment epithelial cells is a powerful cysteine protease inhibitors and plays an important role in normally controlling circulation of proteins in BrM, and the like. However, if advanced glycation end products are excessively accumulated, the expression and secretion of cystatin C proteins are lowered to cause an imbalance of proteolytic action in the RPE basal portion, so that the macular degeneration occurs (IOVS, 2014, 55 (2), 926-34). Therefore, when the production of the advanced glycation end products is inhibited, the macular degeneration may be also prevented (treated).
VEGF (Vascular Endothelial Growth Factor) is secreted from the retinal pigment epithelial cell layer to normally adjust the portion around Bruch's membrane (BrM) and to control growth and compactness of choroid capillary endothelial cells. Under normal conditions the VEGF secretion is very strictly regulated so as to prevent angiogenesis. However, if the VEGF secretion is not strictly regulated, this acts as a critical factor leading to the terminal stage of macular degeneration. If the VEGF secretion abnormally increases, then the abnormal and weak blood vessels which appear in macular degeneration are generated and destroyed (J. Cell. Mol. Med., 17, 7, 833-843, 2013).
Retinal edema occurs, as the retinal capillary blood vessel walls are damaged in an abnormal environment to leach the proteins, red blood cells, and the like present in retinal capillary blood vessels into retinas, which pool in the retinas to cause an edema.
Varicose veins are a disease that veins appear out of skin, where the veins distributed in arms and legs are classified as large deep veins lying between muscles, superficial veins appearing underneath skin and perforating veins linking these two veins, mean among these that the superficial veins stretch and appear to be protruded out of skin, and are developed as the valves making blood flows inside the veins keep constant toward the heart always are damaged with vein walls being weak when the pressure in the varicose veins increases and thus the blood going to the heart is refluxed to stretch the veins.
Peony root is a perennial plant of Ranunculaceae with Radix paeoniae alba and Radix paeoniae rubra. Radix paeoniae alba and Radix paeoniae rubra are determined by the presence or absence of a shell, in which one having the shell is referred to as Radix paeoniae rubra and the other with striped shell to Radix paeoniae alba (Altern. Med. Rev. 6(5), 495-499, 2001). Radix paeoniae alba has, with Radix paeoniae rubra, an inhibitory effect of contraction against stomach and intestine smooth muscles, and uterine smooth muscles, a coronary arterial dilatation effect and effects of preventing atherosclerosis against vascular diseases, lowering blood pressure and improving blood flow. It appears that these effects of peony root extracts are derived from antioxidant effect (J. Ethnopharmacol. 67, 111-119, 1999), platelet anti-aggregating effect (Planta Med, 65, 595-599, 1999), antithrombotic effect (Chem. Pharm. Bull, 35 (2), 849-852, 1987), hyperlipidemia prevention (Fitoterapia, 75(1), 45-49, 2004), and the like. In addition, it has been reported that glycoside, some of components of peony root, is effective in treating cerebral infarction (Zhong Yao Cai, 23 (2), 95-97, 2000).
Licorice is one to dry roots and rhizomes of Glycyrrhiza glabra and G. uralensis and other congeneric plants, as an herbaceous perennial plant belonging to a legume family, and contains flavonoid-based compounds such as liquiritin, including glycyrrhizin of triterpen saponin, as main components. Pharmacological actions include adrenal cortical hormone-like actions, anti-gastric ulcer efficiencies, smooth muscle relaxation actions, liver protective effects, anti-inflammation, anti-allergic effects, antiviral effects (Oriental medicine pharmacology, Jipmoon Dang, 434-436, 2001).
In addition, the antibody (protein) medicines that are currently administrated partly adjust only the mechanism inhibiting neovascular vessels of many factors that cause macular degeneration or retinal edema. Furthermore, it is a well-known fact that they do not completely control this. It is not known for combined natural extract materials containing peony root extracts, or extracts of peony root and licorice which can overcome the limit of therapeutic agents that are currently administrated and control etiologies associated with retinal edema and macular degeneration at the same time.
Accordingly, the present inventors have exerted to develop combined natural extract materials for preventing and treating angioedema including retinal edema, macular degeneration and varicose veins, consequently found that peony root extracts, or mixed extracts of peony root and licorice inhibit generating advanced glycation end products, inhibit breakdown of blood-retinal barriers causing retinal edema in various animal models, protect or treat a sub-retinal region causing dry macular degeneration, and inhibit angiogenesis causing wet macular degeneration, so that the extracts may be usefully used as an active ingredient of the composition for preventing and treating angioedema including macular degeneration, macular edema, retinal edema or varicose veins, and completed the present invention.